الفهرس 
General IntroductionOnly 14 pages are availabe for public view
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Abstract
Glimepiride (Gmp) is a “third-generation” sulphonylurea that is classified as class II according to the Biopharmaceutical Classification System (BCS) due to its poor aqueous solubility and good permeability. This leads to slow Gmp dissolution that may result in irreproducible clinical response or therapeutic failure because of subtherapeutic plasma levels. Vorinostat is widely investigated as a promising anticancer agent for a wide variety of cancers. Yet, vorinostat is categorized as class IV according to BCS due to its poor aqueous solubility and low permeability. In addition, vorinostat has extensive serum clearance and low bioavailability.
The main objectives in this investigation were; firstly, to prepare Gmp with each of tromethamine (Tris) and polyvinylpyrrolidone (PVP-K25) as physical mixtures (PMs), coground mixtures (GMs) and coprecipitates (Coppts) at different drug to carrier ratios (1:2, 1:4, 1:6, and 1:8). With low molecular-weight chitosan (LM-CH), the same binary systems were prepared; however, the Coppts were replaced with kneaded mixtures (KMs). These binary systems were characterized via solubility and solid-state studies. The effects of prepared systems on the in vitro dissolution and the hypoglycemic efficacy of Gmp in rabbits were examined. Secondly, to prepare nanomicellar formulations of vorinostat with poly(ethylene glycol)-block–poly(DL-lactic acid), (PEG-b–PLA). These nanomicelles were characterized with respect to their size, loading, and entrapment efficiencies, and in vitro stability. The effects of these nanomicelles on the bioavaiolability, metabolism and renal excretion of vorinostat in rat serum and urine have been investigated.
The obtained results revealed that the in vitro dissolution as well as the therapeutic efficacy of Gmp were dependent on the type of the carrier, its ratio and the technique followed for preparing the binary systems. Greatly enhanced Gmp dissolution and hypoglycemic efficacy have been found with1:8 Coppt with either Tris or PVP-K25 and 1:8 KM with LM-CH. Mechanism of dissolution enhancement involved Gmp amorphization by PVP-K25 and LM-CH, possible increase in the pH of the microdiffusion layer around the Gmp particles by Tris, and formation of water soluble complexes with the three carriers. Capsules with 1:20 PM with Tris has been selected as promising formulation due to the simple preparation and the significantly increased hypoglycemic efficacy. Also, the obtained results clarified that, nanomicelles with PEG-PLA extremely increased the aqueous solubility of vorinostat by more than 40 times compared with its intrinsic solubility that could facilitate new intravenous formulations of vorinostat. The nanomicelles protected the drug against renal clearance and hepatic biotransformation resulting in prolonged circulating time and highly increased bioavailability after oral and intravenous administrations. The effects on drug solubility and bioavailability were more pronounced with 1:15 nanomicelles possibly due to higher entrapment efficiency and more stable nanomicelles in vivo compared to 1:10 nanomicelles. Nanomicelles of vorinostat with PEG-b-PLA may be suggested as a potential delivery system with improved bioavailability and lower renal and hepatic toxicities